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BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut–liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut–liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut–liver axis of patients with HCV across a fibrosis severity gradient before ( n  = 29) and 6 months after ( n  = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus -mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus -mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii , which correlated with liver disease severity markers. These results develop our understanding of the gut–liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies. Multi-omics analyses of gut microbiome, liver and blood samples from patients with hepatitis C infection before and after removal of the virus reveal metabolic dysregulation along the gut–liver axis.

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.ConclusionIn patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained.Trial registration numberNCT04166383.

This review describes the historical development of an imageable spherical embolic agent and focuses on work performed in collaboration between Biocompatibles UK Ltd (a BTG International group company) and the NIH to demonstrate radiopaque bead utility and bring a commercial offering to market that meets a clinical need. Various chemistries have been investigated and multiple prototypes evaluated in search of an optimized product with the right balance of handling and imaging properties. Herein, we describe the steps taken in the development of DC Bead LUMI™, the first commercially available radiopaque drug-eluting bead, ultimately leading to the first human experience of this novel embolic agent in the treatment of liver tumors.

Background Immunostimulatory effects of PARP inhibitors could increase sensitivity to immune checkpoint inhibitors. The previous Phase II trial (MEDIOLA) reported clinical benefits of durvalumab and olaparib (D + O) in patients with germline BRCA‐mutated (gBRCAm) HER2‐negative metastatic breast cancer. Yet, the clinical activity of D + O in germline BRCA wild‐type (gBRCAwt) triple‐negative breast cancer (TNBC) remains unknown. Methods This single‐arm Phase II study tested D + O in patients with metastatic TNBC. The primary objective was overall response rate (ORR). Secondary objectives were safety, disease control rate (DCR), progression‐free survival (PFS) and overall survival (OS). Based on gBRCA status, patients were assigned to either gBRCAwt or gBRCAm cohort and were treated with D (1500 mg iv q4w) and O (300 mg twice a day orally). Pretreatment fresh tissues and serial blood samples were collected for correlative studies. Results Fifteen patients (12 gBRCAwt and 3 gBRCAm) were enrolled. gBRCAm and gBRCAwt cohorts are reported as a combined dataset because of small sample size due to COVID‐19 and slow accrual. The median number of prior therapies was three (range 0–8). Among 14 RECIST‐evaluable patients (11 gBRCAwt and 3 gBRCAm), ORR was 28.6% (3 gBRCAm and 1 gBRCAwt). DCR was 64.3% (3 gBRCAm and 6 gBRCAwt). The median PFS and OS were 3.6 months (95% confidence interval [CI]: 1.8–5.7) and 10.7 months (95% CI: 5.9–38.9), respectively. There is one gBRCAm patient with ongoing durable PR (67.4+ months). There was no new safety concern. CD83 expression on Types 1 and 2 conventional dendritic cells in blood at baseline was low in the patients with PFS ≥ 4 months compared to those with PFS < 4 months. Conclusion Our study demonstrated modest clinical benefits of D + O with ORR of 28.6% in subsets of heavily pretreated TNBC. Further detailed classification of DCs to understand the predictive role of DCs and prospective validation in a large cohort is required. Trial Registration ClinicalTrials.gov identifier: NCT02484404

Background Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti‐PD1/PD‐L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti‐PD‐L1) and tremelimumab (anti‐CTLA‐4), with and without an interventional radiology (IR) procedure in advanced BTC. Methods Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6‐month progression‐free survival (PFS). Results Twenty‐three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3–3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9–4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5–6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9–40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1–2. Conclusion Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC. The purpose of this study was to explore the efficacy and safety of two ICIs, durvalumab and tremelimumab, with and without an interventional radiology (IR) procedure in patients with advanced BTC. Durva/Treme + IR showed no difference in efficacy compared with Durva/Treme alone, but the safety profile of both cohorts was manageable. Larger studies are needed to fully characterize efficacy of Durva/Treme with or without IR in advanced BTCs.

Cell-free RNAs (cfRNAs) are promising analytes as non-invasive biomarkers and have even greater potential if tied in with metabolomics. Plasma is an optimal source for cfRNAs but is often derived from a variety of anticoagulants. Plasma obtained in heparin is suitable for metabolomics but is difficult to utilize for qPCR-based downstream analysis. In the present study, we aimed to develop a simple, time-efficient, and cost-effective heparinase protocol, followed by library preparation and sequencing of human plasma cfRNAs drawn and stored in heparin at −80 °C for several years. Blood was collected in CPT™ sodium heparin tubes from patients with chronic HCV infection (NCT02400216) at the National Institutes of Health (NIH) Clinical Center. Plasma cfRNAs were treated with heparinase I and used for library preparation and next-generation sequencing (NGS). Heparinase treatment maintained RNA integrity and allowed for successful library preparation for all the study subjects even with 7 ng of cfRNAs as starting material. The classification report derived from Pavian R package v1.2.0 showed no artificial reads. The abundance of chordate over microbial reads suggests no addition of experimental error through heparinase I treatment. We report a novel and practical approach to heparinase treatment for human plasma collected and frozen in sodium heparin for several years. This is an effective demonstration of utilizing heparin plasma for NGS and downstream transcriptomic research, which could then be integrated with metabolomics from the same samples, maximizing efficiency and minimizing blood draws.

Background To evaluate outcomes and survival rates in patients with metastatic adrenocortical carcinoma (ACC) who were treated with image‐guided locoregional treatments (IGLTs). Purpose To evaluate the overall survival (OS) and clinical impact of IGLT in the management of patients with advanced metastatic ACC. Methods Retrospective review of 39 patients treated with IGLT between 1999 and 2018 was performed. Short‐ and long‐term efficacy of treatments were defined based upon imaging and clinical data. Subgroup survival analysis was performed on patients with metastatic disease at diagnosis (N = 17) and compared with the same stage group from the most recent National Cancer Database (NCDB) report. Statistical analysis was performed using Cox proportional hazards model. Results Treatments were performed at different anatomic sites including liver (N = 46), lung (N = 14), retroperitoneum (N = 5), bone (N = 4), subcutaneous (N = 2), and intracaval (N = 1). Radiofrequency, microwave, cryoablation, or a combination of two modalities (45, 18, 3, 3, respectively) were used in 69 ablation sessions. Intra‐arterial procedures were performed in 12 patients in 18 treatment cycles (range 1–3 per patient). As of a 2019 analysis, 11 patients were alive with a mean follow‐up of 169 months (range 63–292 months) from diagnosis. Two‐ and 5‐year OS rates for all patients were 84.5% and 51%, respectively, and 76.5% and 59% for patients with metastatic disease at diagnosis (N = 17). This compares favorably with an NCDB report of 35% 5‐year survival rate for patients with metastatic disease. Female gender and longer time from diagnosis to first IGLT were found to be predictors of prolonged survival with hazard ratios of 0.23 (p < 0.001) and 0.66 (p = 0.001), respectively. Conclusion IGLT may be associated with prolonged life expectancy in select patients with metastatic ACC. Treatment of patients with advanced adrenocortical carcinoma with image‐guided locoregional therapies may be associated with prolonged survival, especially in females. Challenging clinical decisions for this rare disease with few effective treatment options may be informed by our two‐decade experience with locoregional therapies. Such a combined approach with surgery, ablation, and/or embolization may be associated with better than previously reported long‐term patient survivals.

Noncirrhotic portal hypertension (NCPH) is a rare disease that may lead to serious clinical consequences. Currently, noninvasive tools for the assessment of NCPH are absent. We investigated the utility of spleen and liver volumetrics as a marker of the presence and severity of portal hypertension in this population. A cohort of NCPH patients evaluated between 2003 and 2015 was retrospectively studied. The association of spleen and liver volumes with the hepatic venous pressure gradient (HVPG) level was evaluated using locally weighted scatterplot smoothing curves. A cohort of patients with viral hepatitis‐related liver disease was used as controls. Of the 86 patients with NCPH evaluated during the study period, 75 (mean age, 35 ± 17; 73% males) were included in the final analysis. Patients with portal hypertension had significantly higher spleen and liver to body mass index (BMI) ratios compared to patients with HVPG <5 mm Hg (39.5 ± 27.9 versus 22.8 ± 10.6 cm3/kg/m2, P = 0.003; 91.1 ± 40.1 versus 71.4 ± 16.7 cm3/kg/m2, P = 0.014, for spleen/BMI and liver/BMI, respectively). In contrast to the patients with viral hepatitis, a positive linear correlation was observed in the NCPH cohort between spleen/BMI and liver/BMI (above a cutoff of 25 and 80 cm3/kg/m2, respectively) and HVPG level. Additionally, only in the NCPH cohort was an increase in spleen/BMI range quartile predictive of a higher prevalence of portal hypertension and clinically significant portal hypertension (trend, P = 0.014 and 0.031, respectively). Conclusion: Spleen and liver volumetrics may have utility in the assessment of NCPH as a noninvasive biomarker that can be performed using routine radiologic examinations. Further studies are needed to validate these findings. (Hepatology Communications 2018; 00:000‐000) Noncirrhotic portal hypertension is an uncommon and often overlooked cause of portal hypertension. Non‐invasive markers of NCPH are lacking. Spleen and liver volumetrics are shown to correlate with HVPG measurements and may have utility in the assessment of NCPH as a noninvasive biomarker.

Purpose To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors. Methodology LC Bead LUMI™ is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (~260 mg I/ml). 70–150 μ LC Bead LUMI™ iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI™ microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips). Results LC Bead LUMI™ image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post). Conclusion LC Bead LUMI™ image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization.